This invention describes an improved, more economical process for the synthesis of a valuable chemical intermediate (I) ##STR1## used in the manufacture of the antidepressant agent 2[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-4-(2-phenoxyethyl)-2 H-1,2,4-triazol-3(4H)-one which is also known as nefazodone. ##STR2## This subject intermediate, 5-ethyl-4-(2-phenoxyethyl)-1,2,4-triazolone, of Formula I is also known as MJ 14814 and its current synthesis, disclosed in pending application Ser. No. 509,266 and now U.S. Pat. No. 4,487,773 as Example 5, is shown in Scheme 1. An overall yield of 33% for Scheme 1 is predicted from yield calculations of the individual steps in Example 5 of the pending application. ##STR3##
As can be seen in Scheme 1, the preparation of MJ 14814 starts with phenol and ethyl acrylate, an obnoxious material with a high vapor pressure. This process has been successfully scaled up and used repeatedly giving MJ 14814 in 25-30% overall yield from phenol.
MJ 14814 is converted to the antidepressant agent nefazodone (MJ 13754) as disclosed in the above cited pending application. This conversion involves reaction of MJ 14814 with 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride (10) ##STR4##
Preparation of MJ 14814 via Scheme 1 involves six steps and four isolated intermediates, two of which are liquids requiring purification by vacuum distillation. By contrast, the improved process described hereinafter is comprised of four steps involving only three isolated intermediates, all of which are solids, with an overall yield of MJ 14814 of 40-55% from phenol. In comparison, the prior art method, represented by Scheme I, is a longer process requiring more labor and providing MJ 14814 in much lower yield.
The following references relate to component steps of the instant process described herein.
1. Dow Technical Bulletin, "Developmental 2-Ethyl-2-Oxazoline XAS-1454 Ethyloxazoline: An Intermediate for Aminoethylation." This reference describes the synthesis of N-(2-phenoxyethyl)propionamide, an intermediate compound of the instant process.
2. W. Reid and A. Czack, Ann. 676, pp. 121-129 (1964). This reference teaches the reaction of imidoyl ethers with ethyl carbazate to give amidrazones which then cyclize on further heating to 1,2,4-triazoles as outlined below in Scheme 2. ##STR5## However, there is no disclosure of the use of N-substituted imidoyl ethers which would be necessary to obtain a desired N-substituted triazolone. 3. M. Pesson, et al., Bull. Soc. Chim., Fr., pp. 1367-71 (1962). This reference reports a very low yield synthesis (0.3%) of a triazolone with the desired substitution pattern via the process shown below in Scheme 3. ##STR6## The authors state that imidoyl ethers of secondary amides are difficult to make (p. 1364, bottom second column). Pesson, et al., do disclose preparation of a triazolone with the desired substitution pattern but via a synthesis, shown as Scheme 4, which is different from that in the instant process. The reference synthesis begins with an imidoyl ether of a primary amide to give an intermediate carbethoxy hydrazone which is then reacted with a primary amine. ##STR7## Note that the carbazate displaces the imine function in Scheme 4 representing another feature distinguishing from the process of the instant invention.
Pesson, et al., also disclose that thioamides are more reactive than amides, giving N-substituted amidrazones on reaction with carbazate. However, when the N-substituent is alkyl, as required in the instant process, no reaction with ethyl carbazate was observed. Finally, Pesson, et al., teach activation of a thiobenzamide with dimethylsulfate followed by reaction with carbazate to give the triazolone product. Again, there is no disclosure involving activation of alkyl carboxylic acid thioamides, a structural prerequisite for the instant process.
In summary, references 2 and 3 essentially describe reactions of certain amide derivatives with carbazate esters to eventually yield triazolone products but with distinguishing variations in structural relationship to the product produced by the instant process.